Management of toxicity in patients receiving therapy with bevacizumab

Bevacizumab has been administered to more than 200,000 cancer patients globally. This wealth of information has demonstrated that bevacizumab-associated adverse events are similar across indications. Commonly reported events with bevacizumab are hypertension (in up to 34% of patients), proteinuria (in up to 38% of patients) and haemorrhage (mucocutaneous haemorrhage in 20–40% of patients), most of which are grade 1–2 in severity. Less frequent events include arterial and venous thromboembolic events (ATEs, VTEs), congestive heart failure/cardiomyopathy, wound-healing complications and gastrointestinal perforations. These bevacizumab-associated events have also been reported in two phase III trials of bevacizumab in combination with chemotherapy (capecitabine [AVF2119g] or paclitaxel [E2100]) in advanced breast cancer. Overall, these adverse events are not dose-related in any indication (except for hypertension and grade 1 proteinuria). Furthermore, the most frequently reported bevacizumab-associated adverse events are mild/moderate in severity and are easily managed. Recommendations for the management of bevacizumab-related adverse events include regular monitoring (hypertension, proteinuria); use of standard care (hypertension, VTEs); temporary dose interruption (hypertension, proteinuria, VTEs, wound healing) to permanent discontinuation of treatment (for all severe events).     

Repeated treatments with bevacizumab for recurrent radiation necrosis in patients with malignant brain tumors: a report of 2 cases

Bevacizumab is expected to constitute a new treatment modality for radiation necrosis. In the present cases, we observed a recurrence of radiation necrosis after temporary improvement by bevacizumab treatment. Re-treatment with bevacizumab controlled the necrosis again. A 39-year-old male and a 57-year-old female were diagnosed with glioblastoma and lung cancer metastasis, respectively. The former patient underwent partial resection of the glioblastoma, followed by boron neutron capture therapy (BNCT) and 30 Gy of fractionated X-ray radiotherapy. Eleven months after BNCT, he suffered from left hemiparesis and convulsions with enlargement of a perifocal edema. The latter patient underwent stereotactic radiosurgery twice for the same tumor. Three months after the second radiosurgery, she had an uncontrollable convulsion and right hemiplegia with a massive perifocal edema. Both lesions were suggested to be radiation necroses by positron emission tomography using amino acids as a tracer. Neither patient responded to corticosteroids, anticoagulants, or vitamin E. They underwent treatment with 5 mg/kg bevacizumab biweekly, for a total of 6 cycles. The size of the perifocal edema was clearly reduced in response to the treatments. The neurological status of the patients improved concomitant with therapy. However, the clinical status of both patients was aggravated several months after the bevacizumab was stopped, and the perifocal edemas enlarged again. The patients underwent a second treatment with bevacizumab, and the perifocal edemas again decreased. Although radiation necrosis may recur several months after bevacizumab treatment, repeated bevacizumab treatments also appear to be effective.     

Radiosurgery in the treatment of malignant brain tumors

Brain metastases are an attractive target for radiosurgery. Over a period of 6 years, 400 patients with brain metastases have been treated with radiosurgery. Of these patients, 61% had solitary brain metastases and 39% had multiple brain metastases. Local control was achieved in 90% and improvement of severe neurological symptoms in 76%. The median survival time was 8 months. The significant prognostic factors for survival in patients with solitary brain metastases were age, Karnofsky performance status, severity of symptoms, extent of progressive malignant disease outside the brain, histology, interval between diagnosis of primary tumor and brain metastasis, and minimum applied dosage. The significant prognostic factors in patients with multiple brain metastases were sex, Karnofsky performance status and presence of progressive disease outside the brain.     

Radiosurgery in the treatment of malignant brain tumors

Brain metastases are an attractive target for radiosurgery. Over a period of 6 years, 400 patients with brain metastases have been treated with radiosurgery. Of these patients, 61% had solitary brain metastases and 39% had multiple brain metastases. Local control was achieved in 90% and improvement of severe neurological symptoms in 76%. The median survival time was 8 months. The significant prognostic factors for survival in patients with solitary brain metastases were age, Karnofsky performance status, severity of symptoms, extent of progressive malignant disease outside the brain, histology, interval between diagnosis of primary tumor and brain metastasis, and minimum applied dosage. The significant prognostic factors in patients with multiple brain metastases were sex, Karnofsky performance status and presence of progressive disease outside the brain.     

贝伐珠单抗在恶性脑水肿治疗中的应用

以贝伐珠单抗为主的抗血管生成药物通过减少血管通透性和血脑屏障破坏,能有效减轻恶性脑水肿,缓解临床症状,改善患者生命质量。贝伐珠单抗在治疗恶性脑水肿方面取得了积极的疗效,因此被认为是治疗恶性脑水肿的一种安全、有效的治疗手段。     

High dose chemotherapy for the treatment of malignant brain tumors

Conventional treatment of malignant high grade gliomas includes maximal resection followed by external beam radiotherapy. The addition of adjuvant chemotherapy has provided little improvement in the median duration of survival for these patients, particularly those patients with glioblastoma multiforme. The failure of conventional dose chemotherapy to improve the outcome of patients with high grade brain tumors has led several investigators to utilize high dose chemotherapy in order to overcome the limited benefit seen with conventional dose therapy which is due to intrinsic drug resistance as well as the impermeability of blood brain barrier. The majority of published studies utilizing this approach suggest that the addition of high dose chemotherapy with bone marrow transplant is of marginal benefit. However, most of these trials include small numbers of patients with advanced, refractory disease. A few trials have been reported utilizing high dose therapy in an adjuvant setting and the data from these studies are somewhat more promising. This review will analyze these studies and also discuss possible modifications of this approach in order to improve this aggressive treatment for patients who otherwise would have a dismal prognosis.     

Intra-arterial cisplatin in malignant brain tumors: incidence and severity of otic toxicity

Summary Intra-arterial (IA) cisplatin is used to treat gliomas with the goal of maximizing drug concentration in the brain while minimizing systemic toxicity. The present study is based on the author's experience with IA cisplatin administration in 12 patients. The primary goal of the study was to document the extent of otic toxicity in these individuals. Hearing was tested clinically and with audiograms, before each IA cisplatin injection. Eight women and four men with a mean age of 39 years (range 22–61) were treated. Diagnoses included 7 glioblastoma multiformes, 4 anaplastic astrocytomas, and 1 gliosarcoma. Diagnosis was obtained by stereotactic biopsy in four and craniotomy for resection and debulking in eight. The mean number of IA injections per patient was 4.58 (range 3–6). The cisplatin dose was 60 mg/m² with the average dose of cisplatin per cycle being 116 mg (range 96–130 mg). Eleven patients had the agent administered via the internal carotid and one received it by way of a vertebral artery. Nine of the twelve patients (75%) demonstrated pure tone loss, as measured by audiography, of greater than 15 dB in the higher frequencies range ( 3 kHz) bilaterally. One patient became deaf and two others had clinically significant hearing loss. The severity of the auditory damage increased after each administration in each of the cases with clinical abnormality. IA cisplatin may have a role in the treatment of patients with primary malignant brain tumors, but further developments to limit otic toxicity would be of value.     

New development of surgical treatment for malignant brain tumors

The most important prognosticator for malignant brain tumor patients is the degree of tumor removal. On the other hand, surgical removal should not induce aggravation of the patient performance status. In accordance with the result, surgical planning for glioma should be carefully considered. However, there is no standard guide for preoperative planning to date. However, there is no standard guide for preoperative planning to the present. We attempted to divide gliomas into 5 stages according to the difficulty of the surgery and analyzed the relation between the removal rate and each stage. The results demonstrated that the stage is correlated with the removal rate. This staging might contribute to standardization of glioma surgery. For surgical planning of tumors around the motor area, fiber tractography and magnetoencephalography should be very useful. As an intraoperative examination, monitoring of motor evoked potential is necessary to resect tumors around the motor area. For resection of tumors around the speech area, functional brain mapping under awake surgery is the most reliable method. In addition to these techniques for safe surgery, neuro-navigation and chemical navigation using 5-aminolevulinic acid are used to achieve of the maximum removal rate. Finally, development of preoperative examinations, microsurgical technique, and intraoperative monitoring enabled us to do safer and move sure surgery.     

Immunotherapy and biological modifiers for the treatment of malignant brain tumors

The relative ineffectiveness of current therapies for malignant gliomas has led to the need for novel therapeutics. Therapies based on biologic modifiers are among a variety of cancer treatments currently in use or under experimental evaluation and have shown great promise, especially since several potent stimulators of the immune system have been cloned and are now available for clinical use. Early attempts at glioma therapy based on biologic modifiers, however, have failed to demonstrate significant effectiveness. In this review, we select and summarize the results of preclinical and clinical studies published during the past two years that focus on immunotherapy and biologic modifiers for treating gliomas. Despite limited clinical success, we conclude that an increased understanding of molecular biology and immunology from recent studies may pave the way for more effective approaches.     

Organizational principles of the outpatient examination of patients suspected of malignant tumors

Out-patient diagnosis of cancer is carried out in three stages which involve activities of different physicians. Cancer is first suspected by a general practitioner. Prophylactic measures other than examination by specialists and chest photo-roentgenography proved insufficient, and the authors give reasons for this. During the second stage, the patient undergoes further thorough examination which should be well organized to succeed. The third stage, viz. making the final diagnosis, should be performed in an oncologic establishment only.     

Nitrosourea derivatives-induced pulmonary toxicity in patients treated for malignant brain tumors. Early subclinical detection and its prevention

Nitrosourea derivatives, such as BCNU and CCNU, are considered useful chemotherapeutic agents in malignant brain tumors combined therapy. Pulmonary toxicity is one of the more side effects demonstrated both in experimental animal models and in human autoptic findings. Pulmonary fibrosis is the end point of progressive functional disorder of respiratory mechanism and alveolo-capillary gas exchanges. Authors present the results of a randomized, double-blind trial of 40 patients previously treated with surgery and radiotherapy and who subsequently underwent BCNU therapy for primary intracranial glioma. Patients underwent functional respiratory examinations at each chemotherapy course interval. Twenty patients received ambroxol (120 mg/day) for 40 days after chemotherapy course. Control patients received placebo with the same schedule and showed a significant reduction of pulmonary functional parameters (DLCO, MMEF, MEF 25%), whereas in the treated group there is no significant variation of these functional parameters. The mechanism of ambroxol is commonly related to the surfactant synthesis enhancement and to the action on bronchiolar pathways.     

Intrathecal cytosine arabinoside for the treatment of meningeal metastases from malignant brain tumors and systemic tumors

Summary Thirty-two patients with primary or metastatic neoplasms in the ventricular system or subarachnoid space were treated with intrathecal Ara-C. Twenty patients (group I) were treated with single twice-weekly doses; the mean number of doses was 9.7, and the mean total dosage was 165 mg. Six patients received intrathecal Ara-C alone and 14 received concurrent chemotherapy. All four symptomatic patients showed clinical improvement. Malignant cells disappeared from the spinal fluid of six of the 12 patients with positive pretherapy cerebrospinal fluid (CSF) cytology. Two patients were alive with no evidence of recurrence 8 and 16 weeks after beginning therapy, two patients died without demonstrating evidence of recurrence 8 weeks and 9 weeks after starting therapy, 12 patients had recurrences an average of 13 weeks after beginning treatment, and four patients refused further investigation or treatment and died of disease after 6–52 weeks.Pharmacokinetic studies were performed in eight patients. For five patients who received 12 mg Ara-C by injection into an SC-implanted reservior connected to the ventricular system, the CSF disappearance curve was biphasic with half-times of 30 min and 3.5 h.Based on the results of the pharmacokinetic study, an additional 12 patients (group II) were treated on three consecutive days weekly. The mean number of doses was 9.7 and the mean total dosage was 189 mg. Three patients received intrathecal Ara-C alone and nine received concurrent chemotherapy. One of the five symptomatic patients showed clinical improvement. Malignant cells disappeared from the spinal fluid of two of the four patients with positive pretherapy CSF cytology. Four patients were alive with no evidence of recurrence 3–26 weeks after beginning therapy, two patients died within 10 days of beginning treatment without formal re-evaluation, four patients demonstrated progression of tumor an average of 7 weeks after beginning treatment, and two patients changed to another form of therapy because of persistent CSF abnormalities, although there was no radiographic evidence of tumor progression.There were no clear differences in response between group I and group II; however, the groups were not comparable with respect to pathological diagnosis.Intrathecal Ara-C is a promising and relatively safe treatment for malignant disease in the subarachnoid space. Further studies are needed to determine the optimum dose and administration schedule in combination with other intrathecal therapies that may be more active against noncycling G₀ cells.     

Intracarotid infusion of cis-diamminedichloroplatinum in the treatment of recurrent malignant brain tumors

Thirty-five patients with malignant brain tumors (23 with primary brain tumors and 12 with brain metastases) progressing after cranial irradiation +/- chemotherapy received cisplatin, 60 to 120 mg/m2, into the internal carotid artery by a transfemoral approach. Courses of therapy were repeated every 4 weeks. Therapeutic evaluation was performed monthly using the CT scan of the brain and clinical neurologic examination. Thirty patients were evaluable for response. Of 20 evaluable patients with primary malignant brain tumors, 6 responded to therapy and 5 had stable disease. The median time to tumor progression for responding patients was 33 weeks, for stable patients 16 weeks, and 13 weeks for all patients. Five of 10 evaluable patients with brain metastases responded to intracarotid cisplatin, and 2 patients had stable disease. The estimated median time to progression for responding patients was 30+ weeks and 12+ weeks for patients with stable disease. Side effects included seizures in 5 courses, mental agitation and motor restlessness in 1, and transient hemiparesis in 7. One patient may have had a drug-related death, and one patient appeared to develop encephalopathy after treatment. Five patients had clinical deterioration in vision; in two patients it was bilateral. Intracarotid cisplatin has definite activity in patients with malignant primary brain tumors and in patients with brain metastases. The recommended starting dose for intracarotid cisplatin is 60 to 75 mg/m2. At this dose level side effects are uncommon, but includes the risk of neurologic and retinal toxicity.     

Cardiac toxicity after radiation therapy for 52 patients with malignant thymic tumors

Complete surgical resection is the first choice for all malignant thymic tumors and has a better prognosis. Myojin[1] reported 5-year survival rates for Masaoka Stage III thymoma of 86%. Radical or adjuvant radiotherapy is recommended when surgery is impossible or thymomas could not be completely resected. The results of radiation therapy for invasive thymomas are also satisfactory[2, 3]. However, late side effects of radiation therapy, such as second malignant tumors and radiation-induced h…     

Current indications of chemotherapy in the treatment of malignant brain tumors in children

The prognosis of childhood brain tumors is severe because of a high tumor-related mortality and a poor quality of life in some of the survivors. Chemotherapy is expected to cure more patients but also to reduce the effect of radiation therapy. Till now, the benefit due to chemotherapy in the treatment of these tumors has been minimal but future perspectives are encouraging.     

Resent advances in chemotherapy for malignant brain tumors

Most malignant brain tumors are resistant to the chemotherapeutic agents because of the existence of several mechanisms or substances such as the blood-brain barrier, genes and proteins. Recently many studies have been started to overcome the chemoresistance. Especially recent advances in the field of molecular biology have contributed to examination of the chemosensitivities of tumor cells. Trials for the individualization of the treatment, so-called Taylor-made therapy, is one of these challenges. Loss of chromosome 1 p and 19 q is considered to be closely related to chemosensitivity in anaplastic oligodendrogliomas. This is one of the breakthroughs in the field of chemotherapy for malignant brain tumors. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme which reduces the cytocidal effect of nitrosourea. In order to overcome the chemoresistance, drugs except nitrosourea or some drugs which reduce the MGMT activity are used for tumors expressing MGMT. New technology targeting growth factor receptor such as EGFR or VEGFR is also applied to cancer chemotherapy. On the other hand, multi-institutional cooperative studies have been started to obtain evidence in cancer treatment. Phase II study for a small number of patients is not sufficient to demonstrate the efficacy of the treatment and to establish the standard therapy. Multi-institutional randomized controlled study by JCOG Brain Tumor Study Group is the first trial for the treatment of malignant astrocytomas under well-established quality control and quality assurance systems. It can be a model of clinical trials for malignant brain tumors in Japan.     

Characteristics and immunologic changes in patients with malignant brain tumors

The investigation was concerned with assaying immunity and evaluating the role played by monocytes and tumor cells in the formation of T-cell dysfunction in malignant glioma (MG). The study group included 28 patients with anaplastic astrocytomas (n = 18) and glioblastomas (n = 10). MG patients showed significant changes in the numbers of CD16+ NK-cells and HLA-DR monocytes as well as lowered levels of HLA-DR expression on monocytes and proliferative response of T-lymphocytes as compared with both standard and alternative pathways of activation. Monocytes and macrophages suppressed T-cell activity due to production of prostaglandins E2 in such patients. Enhanced immunosuppression was also reported in 24-hour supernatants of tumor cells. Immune disorders were shown to involve apoptosis-independent mechanisms. Hence, despite the immune privilege of the brain, immunocompetent cells crossed blood-brain barrier and counteracted with tumor cells. As a consequence, monocyte function and cellular cooperation dropped while production of immunosuppressive factors rose, and T-cell dysfunction was brought about through apoptosis-independent mechanisms.     

Local treatment of malignant brain tumors using implantable chemotherapeutic polymers

Malignant gliomas are among the most devastating human cancers. The infiltrating nature of these malignancies makes complete surgical resection nearly impossible. Conventional therapy for malignant gliomas consists primarily of surgical debulking followed by radiation therapy and possibly chemotherapy. The major factor limiting intracranial therapeutic levels of systemically administered chemotherapeutics is the physiologic barriers of the brain. This has led to the development of novel methods of drug delivery such as implantable polymers containing chemotherapeutic agents. Several phase III clinical trials show that implantation of carmustine-containing biodegradable polymers prolongs survival in patients with both recurrent and newly diagnosed malignant gliomas. In this article, we summarize these trials and discuss ongoing clinical trials involving implantable chemotherapy-containing polymers in the treatment of patients with malignant gliomas.